Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06/19/2026 has been entered.
DETAILED ACTION
Claims 2 and 10-14 are canceled. Claims 15-16 are new. Claims 1, 3-9 and 15-16 are pending and under consideration in this action.
Priority
The instant claims are entitled to an effective filing date of 02/28/2020.
Drawings
The drawings are objected to because figures 16A-C are illegible. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 15 is objected to because of the following informalities: Claim 15 recites “claim 1 wherein” which is missing a comma before the wherein clause.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 15-16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. The amendment filed on 06/19/2026 has introduced new matter into the claims.
Claim 15, as filed on 06/19/2026, recites the method of claim 1 wherein the subject has antibiotic-induced dysbiosis.
Claim 16, as filed on 06/19/2026, recites the method of claim 3, wherein the subject has antibiotic-induced dysbiosis.
Applicant has not pointed out where the amended claims are supported, nor does there appear to be a written description of the claim limitation that requires the subject to have antibiotic-induced dysbiosis.
Claims 15-16 contain new matter because claims 15 and 16 require the subject of claims 1 and 3 respectively to have antibiotic-induced dysbiosis. Claims 1 and 3 separately require a human subject, and the claims require a step of determining the type of bacteria associated with health that are either missing or diminished in the subject’s stool and/or urine sample and administering a composition comprising one or more of the missing or diminished types of bacteria to the subject. Therefore, claims 15-16 require support for such methods in which the human subject has antibiotic-induced dysbiosis. In other words, claims 15-16 require determining the type of bacteria associated with health that are either missing or diminished in the [human that has antibiotic-induced dysbiosis] subject’s stool and/or urine sample and administering a composition comprising one or more of the missing or diminished types of bacteria to the subject.
The specification as filed and the original claims do not provide support for the limitations in claims 15-16. The specification teaches administering compositions to specific categories of subjects. In some embodiments, the pharmaceutical composition can be administered to a subject who is not taking an antibiotic compound. See [0064]. In example 2, the specification discloses that no participant had antibiotic exposure within at least one month prior to sample collection and none reported having undergone medical procedures and/or supplementation resulting in a significantly altered intestinal microbiome composition. See [0045]. In example 3, the specification teaches determining the nature and location of dysbiosis associated with USD. The specification teaches conducting a microbiome analysis from the gastrointestinal and urinary tracts of subjects with an active episode of USD or no history of the disease. Higher rates of antibiotic use among USD patients along with integrated microbiome and metabolomic results support the hypothesis that USD is associated with an antibiotic-driven shift in the microbiome from one that protects against USD to one that promotes the disease. Furthermore, the specification suggests that antibiotics produce a long-term shift in the microbiome that may increase the risk for USD, with the urinary tract microbiome holding more relevance for USD than the gut microbiome. See [0068]. As shown in table 8, the patients described in example 3 include healthy and USD patients that used antibiotics in the last 12 months and in the past 30 days. The specification discloses that the urinary tract microbiome differed by antibiotic use for 12 months. However, urinary tract microbiota composition did not differ significantly by 30-day antibiotic use. See [0077]. Neither 30-day nor 12-month antibiotic use had a significant correlation to O. formigenes colonization. See [0078]. As such, the specification and the original claims do not teach determining a type of bacteria that are either missing or diminished in the stool and/or urine of a subject with antibiotic-induced dysbiosis; nor does the disclosure teach subjects with antibiotic-induced dysbiosis that are administered a composition comprising one or more of types of bacteria that are missing or diminished in the subject’s stool and/or urine sample.
Such limitations recited in the instant claims 15-16, which did not appear in the specification or original claims, as filed, introduce new concepts and violate the description requirement of the first paragraph of 35 U.S.C 112. Applicant is required to provide sufficient written support for the limitations recited in the instant claims. Applicant can remove the new matter limitations from the claims to obviate this rejection.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 3-9 and 15-16 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 3 recites the limitation “the network” in line 6. There is insufficient antecedent basis for this limitation in the claim. In one interpretation, “the network” refers to all of the bacteria present in the stool and/or urine sample; and under an alternative interpretation, “the network” is a subset of the bacteria known to be associated with oxalate metabolism.
Claims 4-9 and 16 depend from claim 1 and are rejected for the reason set forth above.
Claims 15-16 recite “antibiotic-induced dysbiosis”, which renders the claims indefinite because it is unclear whether the dysbiosis is required to be present in the stool and/or urine. Claims 15 and 16 depend from claims 1 and 3 respectively. Claims 1 and 3 require determining the type of bacteria associated with health that are either missing or diminished in the subject’s stool and/or urine sample. Therefore, in one interpretation the missing or diminished bacteria are indicative of antibiotic-induced dysbiosis. However, the claims and the specification do not describe stool and/or urine compositions associated with antibiotic-induced dysbiosis. Therefore, under an alternative interpretation claims 15-16 require the subject to have an antibiotic-induced dysbiosis in any microbiome native to the subject prior to the 16S RNA sequencing or shotgun metagenomic sequencing step.
Response to Arguments
The declaration under 37 CFR 1.130(a) filed 06/19/2026 has disqualified Zampini (Scientific Reports, 2019 Apr. 1, 9(1), 5425) as prior art under 102(a)(1), because the declaration establishes that the subject matter disclosed in Zampini was obtained directly or indirectly from the joint inventors of the application, Aaron Miller and Monoj Monga, and the declaration provides a reasonable explanation of Anna Zampini, Andrew Nguyen, and Emily Rose’s involvement with the journal article.
Applicant’s arguments, see the remarks p. 4 para. 4, filed 06/19/2026, with respect to the rejection of claims 1, 3-4, and 6 under 35 U.S.C. 103 have been fully considered and are persuasive. Applicant asserts that the declaration under 37 USC 1.130 disqualifies Zampini as a prior art reference (p. 4 para. 4).
Accordingly, the rejection of claims 1, 3-4, and 6 under 35 U.S.C. 103 as being unpatentable over Zampini in view of Campieri is withdrawn. However, new grounds of rejections are made in view of newly found prior art references.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 3-4, and 6-8 are rejected under 35 U.S.C. 103 as being unpatentable over Suryavanshi (Sci Rep 6, 34712 (2016)) in view of Kaul (US 2010/0028422, as previously relied upon 12/16/2024)
Regarding claim 1, Suryavanshi teaches associating oxalate metabolizing bacteria species (OMBS) in the human gut with hyperoxaluria. See the abstract. Suryavanshi teaches collecting urine and fecal samples from 24 kidney stone diseased [human] patients and 15 healthy control subjects. See p. 11 para. 4. Suryavanshi teaches using 16S rRNA gene sequencing to assess differences between the composition of the gut microbiota in individuals with recurrent kidney stones, which is a symptomatic phase of hyperoxaluria, and healthy individuals. See p. 2 para. 1. In figure 7, Suryavanshi shows a heatmap (i.e. a profile) representing common bacterial genera detected through 16S rRNA. Suryavanshi teaches grouping sequences into operational taxonomic units. Suryavanshi teaches applying a Mann-Whitey U test (i.e. differential abundance) and observing differences at phylum and class level abundance. See the paragraph spanning pgs. 2-3. Suryavanshi suggests that there is a depletion in Oxalobacter formigenes in subjects with kidney stones. Suyavanshi teaches obtaining the contribution of O. formigenes to the total OMBS population with the help of a ratio of Oxalobacter copy number to formyl-CoA transferase (frc)-gene copy number. Suyavanshi suggests that there is a higher ratio of Oxalobacter formigenes in healthy subjects ranging from 1.2 to 88.13%, and a lower ratio in kidney stone disease patients ranging from 0.004 to 0.22% (i.e. ratio of 1.2-88.13 to 0.004-0.22 of health to bacteria associated with hyperoxaluria). See p. 9 last paragraph. Suryavanshi states that there is: a direct link between lack of colonization of O. formigenes as a major risk factor and inverse association with calcium oxalate kidney stones in human. See p. 1 last two lines.
Suryavanshi does not teach administering a composition comprising one or more of the missing or diminished types of bacteria to the subject.
Kaul teaches a method for preventing or treating an oxalate-related condition comprising, administering to a human or animal an effective amount of a composition comprising an oral delivery vehicle comprising an oxalate reducing composition comprising oxalate reducing bacteria. See claim 125 of Kaul. The oxalate reducing bacteria is Oxalobacter formigenes. See claim 131 of Kaul. The oxalate related condition is selected from a group that includes hyperoxaluria, and idiopathic calcium oxalate kidney stone disease. See claim 139. Kaul suggests that consumption of O. formigenes is well tolerated by healthy volunteers and primary hyperoxaluria patients. See [0166].
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to apply the Oxalobacter formigenes administration of Kaul to Suryavanshi’s subjects with hyperoxaluria. One of ordinary skill in the art would have been motivated to do so because Kaul suggests that the O. formigenes is well tolerated by subjects with hyperoxaluria and healthy subjects. There would have been a reasonable expectation of success because Suryavanshi suggests that O. formigenes is a potential probiotic in treatment of hyperoxaluria (see p. 10 para. 4); and Kaul teaches treating hyperoxaluria with O. formigenes (see e.g. claim 131).
Regarding claim 3, Suryavanshi states that there is: a direct link between lack of colonization of O. formigenes as a major risk factor and inverse association with calcium oxalate kidney stones in human. See p. 1 last two lines. Suryavanshi teaches collecting urine and fecal samples from 24 kidney stone diseased [human] patients and 15 healthy control subjects. See p. 11 para. 4. Suryavanshi teaches using 16S rRNA gene sequencing to assess differences between the composition of the gut microbiota in individuals with recurrent kidney stones, which is a symptomatic phase of hyperoxaluria, and healthy individuals. See p. 2 para. 1. In figure 7, Suryavanshi shows a heatmap (i.e. a profile) representing common bacterial genera detected through 16S rRNA. Suryavanshi teaches grouping sequences into operational taxonomic units. Suryavanshi teaches applying a Mann-Whitey U test (i.e. differential abundance) and observing differences at phylum and class level abundance. See the paragraph spanning pgs. 2-3. Suryavanshi teaches performing a network analysis in order to detect microbial interactions in the gut due to microbial dysbiosis in kidney stone disease subjects. See p. 4 para. 1. Suryavanshi suggests that there is a depletion in Oxalobacter formigenes in kidney stone subjects. Suyavanshi teaches obtaining the contribution of O. formigenes to the total OMBS population with the help of a ratio of Oxalobacter copy number to frc-gene copy number. Suyavanshi suggests that there is a higher ratio of Oxalobacter formigenes in healthy subjects ranging from 1.2 to 88.13%, and a lower ratio in kidney stone disease patients ranging from 0.004 to 0.22%. See p. 9 last paragraph.
Suryavanshi does not teach: decreasing but not preventing the risk that a human subject will develop urinary stone disease or hyperoxaluria.
Suryavanshi does not teach administering a composition comprising one or more of the missing or diminished types of bacteria to the subject.
Kaul teaches methods which reduce the risk for developing oxalate-related disorders by reducing the amount of oxalate in the gastrointestinal tract. See [0010]. A reduction in oxalate absorption is achieved by supplying oxalate degrading bacteria to the gastrointestinal tract. These bacteria are Oxalobacter formigenes. See [0011]. In example 1, Kaul teaches treating high risk patients. Kaul teaches feeding primary hyperoxaluric patients capsules containing O. formigenes in example 1. See [0098]. Kaul suggests that consumption of O. formigenes is well tolerated by healthy volunteers and primary hyperoxaluria patients. See [0166].
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to apply the Oxalobacter formigenes administration technique of Kaul to Suryavanshi’s subjects. One of ordinary skill in the art would have been motivated to do so because Kaul suggests that the O. formigenes is well tolerated by primary hyperoxaluria patients and healthy volunteers. There would have been a reasonable expectation of success because Suryavanshi teaches a subject population with reduced O. formigenes (e.g. see p. 9 last paragraph); and Kaul suggests that administering O. formigenes can reduce the risk of developing oxalate-related disorders.
Regarding claims 4 and 6, Suyavanshi discloses that all healthy subjects and only 4 kidney stone disease subjects are found to be colonized with Oxalobacter formigenes. See p. 5 para. 1 and see figure S6. Suyavanshi that there is a higher ratio of Oxalobacter formigenes in healthy subjects ranging from 1.2 to 88.13%, and a lower ratio in kidney stone disease patients ranging from 0.004 to 0.22%. See p. 9 last paragraph.
Kaul teaches that absence of O. formigenes is a risk factor in oxalate related disorders. See [0071]. Kaul teaches feeding primary hyperoxaluric patients capsules containing O. formigenes in example 1. See [0098].
Regarding claim 7, Kaul teaches a method for preventing or treating an oxalate related condition comprising administering to a human or animal a composition comprising an oxalate reducing bacteria, a disaccharide, maltodextrin, alginate and oligofructose (i.e. prebiotic). See claim 125 of Kaul.
Regarding claim 8, in example 3 Kaul teaches feeding a group of rats a capsule twice a day and oxalate diet overnight. See [0121]. Kaul indicates that the capsule includes Oxalobacter formigenes. See [0117]. In example 6 Kaul teaches administering O. formigenes capsules to rats by gavage, and feeding the rats a standard diet supplemented with oxalate. See [0156].
Suyavansh and Kaul do not teach a composition that further comprises the prebiotic oxalate. However, Kaul teaches separate administrations of O. formigenes, and an oxalate prebiotic.
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to combine Kaul’s oxalate with the O. formigenes. One of ordinary skill in the art would have been motivated to do so because Kaul teaches comprising substrates (see [0041]); and Kaul discloses that Oxalobacter formigenes uses oxalate as a substrate (see [0011]). There would be a reasonable expectation of success because Kaul demonstrates feeding rats an oxalate diet with O. formigenes capsules.
Claims 5 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Suryavanshi (Sci Rep 6, 34712 (2016)) in view of Kaul (US 2010/0028422), as applied to claims 1, 3-4 and 6-8 above, and further in view of Miller (MSystems, 2017, 2(5), 10-1128; as previously relied upon), hereafter Miller2017, with evidence from Miller (Applied and environmental microbiology, 2016, 82(9), 2669-2675; as previously provided with the action mailed 12/16/2024) hereafter Miller2016.
Regarding claim 5, Suryavanshi, in figure 7, discloses that Ruminococcus is diminished in kidney stone disease patients with a family history (KSD_FH) compared to healthy control subjects (HLT).
Kaul teaches compositions for oral administration. The compositions release oxalate degrading microbes. See [0019]. Kaul teaches oxalate-degrading bacteria t including Lactobacilli and O. formigenes. See [0077].
Suryavanshi and Kaul do not teach administering to the subject a composition comprising one or more of the missing or diminished bacteria selected from the following (i) one or more species of bacteria falling under the genus Ruminococcus; (ii) one or more species of bacteria falling under the genus Enterobacter; (iii) Bacteroides acidofaciens; (iv) Bacteroides vulgatus; and (v) Bacteroides dorei.
Miller2017 teaches developing targeting bacteriotherapies to reduce urinary oxalate excretion in patients at risk for recurrent calcium oxalate stones. See the last sentence of the abstract. Miller2017 teaches transplanting NA feces, that is, the whole fecal microbial community from N. albigula into a model mammalian host, the Sprague-Dawley rat. See p. 2 results section first paragraph. Miller2017 discloses that the NA bacteria include Lactobacillus reuteri, L. animalis, L. johnsonii, gasseri, and Enterococcus gallinarum. See table 3. Miller2017 teaches that Ruminococcus is positively correlated with the relative abundance of Oxalobacteraceae. See table S1. Ruminococcus is prevalent in the N. albigula gut, as evidenced by Miller2016 (p. 2669 right column first passage). The N. albigula (NA) feces group of Miller2017 exhibits a 66% reduction in urinary oxalate after 3 days of consecutive transplants, which is on par with studies that administer daily oral doses of O. formigenes for up to 4 weeks. See the discussion section first paragraph. Furthermore, Miller2017 suggests that when humans are administered oxalate-degrading bacteria orally, these microbes typically persist in the gut for only a few days or a week before becoming undetectable in the feces. See p. 2 paragraph 2.
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to apply Miller2017’s Ruminococcus administration technique to the subjects of Suryavanshi and Kaul. One of ordinary skill in the art would have been motivated to do so because Kaul teaches orally administering oxalate-degrading bacteria; and Miller2017 suggests that orally administered oxalate-degrading bacteria may become undetectable in only a few days or a week. Furthermore, Miller2017 suggests that administering NA feces, which contains Ruminococcus, can reduce urinary oxalate on par with daily oral doses of O. formigenes. There would have been a reasonable expectation of success because Miller2017 demonstrates administering the feces to a model mammal.
Regarding claim 9, Miller2017 teaches transplanting NA feces, that is, the whole fecal microbial community from N. albigula into a model mammalian host, the Sprague-Dawley rat. See p. 2 results section first paragraph.
Claims 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Suryavanshi (Sci Rep 6, 34712 (2016)) and Kaul (US 2010/0028422, as previously relied upon 12/16/2024), as applied to claims 1, 3-4 and 6-8 above, and further in view of Tasian (J Am Soc Nephrol. 2018 Jun;29(6):1731-1740).
Regarding claim 15 and 16, Suryavanshi teaches kidney stone diseased patients. See p. 11 para. 4. Furthermore, Suryavanshi discloses that recurrent kidney stones are a symptomatic phase of hyperoxaluria. See p. 2 para. 1. Furthermore, Suryavanshi suggests that hyperoxaluria leads to dysbiosis. See, e.g. the title.
Kaul teaches preventing or treating an oxalate-related condition comprising administering to a human an effective amount of a composition comprising an oxalate reducing bacteria. See claim 125 of Kaul.
Suryavanshi and Kaul do not teach the subject that has antibiotic-induced dysbiosis.
Tasian teaches associating antibiotics and nephrolithiasis (i.e. kidney stones). See the abstract methods. Tasian teaches patients with nephrolithiasis exposed to antibiotics. See p. 1733 right column para. 1. Tasian discloses that antibiotics change the composition of the intestinal microbiome (i.e. dysbiosis). See p, 1735 first passage. Tasian suggests that antibiotics may be contributing to the increasing prevalence and earlier age at onset of nephrolithiasis. See p. 1734 right column last full paragraph.
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to substitute Tasian’s patients with antibiotic-induced dysbiosis for Suryavanshi’s kidney stone diseased patients. One of ordinary skill in the art would have been motivated to do so because Tasian suggests that the population is at risk of nephrolithiasis. There would have been a reasonable expectation of success because Suryavanshi demonstrates performing 16S RNA sequencing on urine and stool samples from patients with dysbiosis.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KIMBERLY C BREEN whose telephone number is (571)272-0980. The examiner can normally be reached M-Th 7:30-4:30, F 8:30-1:30 (EDT/EST).
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/K.C.B./Examiner, Art Unit 1657
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